Cold exposure modulates potential brown adipokines in humans, but only FGF21 is associated with brown adipose tissue volume.

OBJECTIVE: The study objective was to investigate the effect of cold exposure on the plasma levels of five potential human brown adipokines (chemokine ligand 14 [CXCL14], growth differentiation factor 15 [GDF15], fibroblast growth factor 21 [FGF21], interleukin 6 [IL6], and bone morphogenic protein 8b [BMP8b]) and to study whether such cold-induced effects are related to brown adipose tissue (BAT) volume, activity, or radiodensity in young humans. METHODS: Plasma levels of brown adipokines were measured before and 1 h and 2 h after starting an individualized cold exposure in 30 young adults (60% women, 21.9 ± 2.3 y; 24.9 ± 5.1 kg/m2 ). BAT volume, 18 F-fluorodeoxyglucose uptake, and radiodensity were assessed by a static positron emission tomography-computerized tomography scan after cold exposure. RESULTS: Cold exposure increased the concentration of CXCL14 (Δ2h = 0.58 ± 0.98 ng/mL; p = 0.007), GDF15 (Δ2h = 19.63 ± 46.2 pg/mL; p = 0.013), FGF21 (Δ2h = 33.72 ± 55.13 pg/mL; p = 0.003), and IL6 (Δ1h = 1.98 ± 3.56 pg/mL; p = 0.048) and reduced BMP8b (Δ2h = -37.12 ± 83.53 pg/mL; p = 0.022). The cold-induced increase in plasma FGF21 was positively associated with BAT volume (Δ2h: ß = 0.456; R2 = 0.307; p = 0.001), but not with 18 F-fluorodeoxyglucose uptake or radiodensity. None of the changes in the other studied brown adipokines was related to BAT volume, activity, or radiodensity. CONCLUSIONS: Cold exposure modulates plasma levels of several potential brown adipokines in humans, whereas only cold-induced changes in FGF21 levels are associated with BAT volume. These findings suggest that human BAT might contribute to the circulatory pool of FGF21.

Serum levels of the novel adipokine isthmin-1 are associated with obesity in pubertal boys.

OBJECTIVES: To evaluate whether there is an association between the serum levels of the novel insulin-like adipokine isthmin-1 (ISM1) and obesity-related phenotypes in a population of Spanish children and to investigate the plausible molecular alterations behind the alteration of the serum levels of this protein in children with obesity. METHODS: The study population is a sub-cohort of the PUBMEP research project, consisting of a cross-sectional population of 119 pubertal children with overweight (17 boys, 19 girls), obesity (20 boys, 25 girls), and normal weight (17 boys, 21 girls). All subjects were classified into experimental groups according to their sex, obesity, and insulin resistance (IR) status. They were counted anthropometry, glucose and lipid metabolism, inflammation and cardiovascular biomarkers as well as isthmin-1 (ISM1) serum levels. This population was intended as a discovery population to elucidate the relationship between obesity and ISM1 levels in children. Furthermore, the study population had blood whole-genome DNA methylation examined, allowing deepening into the obesity-ISM1 molecular relationship. RESULTS: Higher serum ISM1 levels were observed in boys with obesity than in normal weight (P = 0.004) and overweight (P = 0.007) boys. ISM1 serum levels were positively associated with body mass index (BMI) Z-score (P = 0.005) and fat mass (P = 0.058) and negatively associated with myeloperoxidase (MPO) (P = 0.043) in boys. Although we did not find associations between ISM1 serum levels and metabolic outcomes in girls, which may indicate a putative sexual dimorphism, fat mass was positively associated in all children, including boys and girls (P = 0.011). DNA methylation levels in two-enhancer-related CpG sites of ISM1 (cg03304641 and cg14269097) were associated with serum levels of ISM1 in children. CONCLUSIONS: ISM1 is associated with obesity in boys at the pubertal stage, elucidating how this protein might be of special relevance as a new biomarker of obesity in children. Further studies including a longitudinal design during puberty are needed.

Development and Validation of a Clinical-Genetic Risk Score to Predict Hepatic Encephalopathy in Patients With Liver Cirrhosis.

INTRODUCTION: We aimed to define the impact of the genetic background on overt hepatic encephalopathy (HE) in patients with liver cirrhosis by developing a combined clinical-genetic risk score. METHODS: Patients suffering from liver cirrhosis from the outpatient clinics of 4 hospitals (n = 600) were included and followed up for at least 5 years until HE bouts, liver transplant, or death. Patients were genotyped for 60 candidate single nucleotide polymorphisms together with the microsatellite in the promoter region of the gene GLS. RESULTS: Single nucleotide polymorphisms rs601338 (FUT2), rs5743836 (TRL9), rs2562582 (SLC1A3), rs313853 (SLC1A5), and GLS microsatellite did predict independently the incidence and severity of overt HE and were included as genetic score. Competing risk analysis revealed that bilirubin (subhazard ratio [sHR] 1.30 [1.15-1.48], P < 0.001), albumin (sHR 0.90 [0.86-0.93], P < 0.001), genetic score (sHR 1.90 [1.57-2.30], P < 0.001), and previous episodes of overt HE (sHR 2.60 [1.57-4.29], P < 0.001) were independently associated to HE bouts during the follow-up with an internal (C-index 0.83) and external validation (C-index 0.74). Patients in the low-risk group had 5% and 12% risk of HE at 1 (log-rank 92.1; P < 0.001) and 5 (log-rank 124.1; P < 0.001) years, respectively, whereas 36% and 48% in the high-risk group. DISCUSSION: The genetic background influenced overt HE risk and severity. The clinical-genetic HE Risk score, which combined genetic background together with albumin, bilirubin, and previous episodes of overt HE, could be a useful tool to predict overt HE in patients with cirrhosis.

Hepatitis C Virus Clearance by Direct-Acting Antivirals Agents Improves Endothelial Dysfunction and Subclinical Atherosclerosis: HEPCAR Study.

INTRODUCTION: Hepatitis C virus (HCV) infection has been related to increased cardiovascular (CV) risk. The aim of this study was to analyze the impact of sustained virological response (SVR) on endothelial dysfunction and subclinical atherosclerosis in patients with hepatitis C virus treated with direct-acting antiviral agents. METHODS: A total of 114 patients were prospectively recruited and underwent CV risk assessment including (i) endothelial dysfunction determined through laser Doppler flowmetry and (ii) subclinical atherosclerosis, elucidated by the ankle-brachial index (ABI). Atherogenic lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides); markers of oxidative stress (oxidized low-density lipoprotein antibodies [OLAbs]), soluble markers of adhesion (vascular cell adhesion molecule [VCAM], e-selectin, and soluble markers of angiogenesis; and vascular endothelial growth factor, endothelial [EMPs] and platelet [PMPs] apoptotic microparticles, and cell-free DNA [cfDNA]) were measured. All determinations were performed at baseline, 12 weeks (SVR time), and 1 year after treatment. RESULTS: In patients with endothelial dysfunction, area of hyperemia improved after virus clearance (P = 0.013) and was related to significant decrease in VCAM, e-selectin (P < 0.001), and cfDNA (P = 0.017) and to increased OLAb levels (P = 0.001). In patients with subclinical atherosclerosis at baseline, a significantly improved ABI was seen after HCV clearance (P < 0.001). Levels of both EMPs and PMPs also decreased after SVR and at follow-up (P = 0.006 and P = 0.002, respectively). DISCUSSION: HCV clearance improved not only liver function but also endothelial dysfunction and subclinical atherosclerosis promoted by decrease in levels of VCAM, e-selectin, cfDNA, and PMPs and EMPs.

Negative predictive value of the repeated absence of gluten immunogenic peptides in the urine of treated celiac patients in predicting mucosal healing: new proposals for follow-up in celiac disease.

BACKGROUND: The treatment of celiac disease (CD) is a lifelong gluten-free diet (GFD). The current methods for monitoring GFD conformance, such as a dietary questionnaire or serology tests, may be inaccurate in detecting dietary transgressions, and duodenal biopsies are invasive, expensive, and not a routine monitoring technique. OBJECTIVES: Our aim was to determine the clinical usefulness of urine gluten immunogenic peptides (GIP) as a biomarker monitoring GFD adherence in celiac patients and to evaluate the concordance of the results with the degree of mucosal damage. METHODS: A prospective observational study was conducted involving 22 de novo CD patients, 77 celiac patients consuming a GFD, and 13 nonceliac subjects. On 3 d of the week, urine samples were collected and the GIP concentrations were tested. Simultaneously, anti-tissue transglutaminase antibodies, questionnaire results, clinical manifestations, and histological findings were analyzed. RESULTS: Approximately 24% (18 of 76) of the celiac patients consuming a GFD exhibited Marsh II-III mucosal damage. Among this population, 94% (17 of 18) had detectable urine GIP; however, between 60% and 80% were asymptomatic and exhibited negative serology and appropriate GFD adherence based on the questionnaire. In contrast, 97% (31 of 32) of the celiac patients without duodenal damage had no detectable GIP. These results demonstrated the high sensitivity (94%) and negative predictive value (97%) of GIP measurements in relation to duodenal biopsy findings. In the de novo CD-diagnosed cohort, 82% (18 of 22) of patients had measurable amounts of GIP in the urine. CONCLUSIONS: Determining GIP concentrations in several urine samples may be an especially convenient approach to assess recent gluten exposure in celiac patients and appears to accurately predict the absence of histological lesions. The introduction of GIP testing as an assessment technique for GFD adherence may help in ascertaining dietary compliance and to target the most suitable intervention during follow-up.

Sedentarism, Physical Activity, Steps, and Neurotrophic Factors in Obese Children.

PURPOSE: This study aimed to examine the associations of sedentary time, physical activity (PA) and step-related behaviors with neurotrophic growth factors. METHODS: A total of 97 children with overweight/obesity age 8 to 11 yr participated in this study. Sedentary time, PA, and steps were measured by GT3X+ accelerometers in hip and nondominant wrist. Estimates of light, moderate, vigorous, and moderate-to-vigorous PA (MVPA) were obtained. Steps per daytime, peak 60-, 30-, and 1-min cadence were computed. The time accumulated (min·d) in different cadence bands of steps was also computed from hip accelerometer. Plasma levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin growth factor-1 (IGF-1) were determined by the XMap technology (Luminex IS 100/200 system, Luminex Corporation, Austin, TX). RESULTS: Light PA, moderate PA, MVPA, and the peak 60-min cadence were positively related with BDNF concentrations (all P < 0.05), and only light PA to VEGF (P = 0.048). No association was observed for IGF-1 (P > 0.05). The associations of light PA with BDNF and VEGF disappeared (all P > 0.05) after performing analyses with nondominant wrist-placement data. However, moderate PA and MVPA remained significantly associated with BDNF (both P < 0.05). The time accumulated in cadence bands of 40 to 59 steps per day and 60 to 79 steps per day (i.e., walking at slow pace) was positively associated with plasma BDNF (all P < 0.05). CONCLUSIONS: In conclusion, PA is positively related to plasma BDNF, whereas no relationship was observed for VEGF or IGF-1. Higher amounts of time spent in slow walking cadence bands could increment BDNF levels. Exercise-based randomized controlled trials in children with overweight/obesity should be carried out to better understand the influence of PA behaviors on the neurotrophic factors.

Normal or High Polyphenol Concentration in Orange Juice Affects Antioxidant Activity, Blood Pressure, and Body Weight in Obese or Overweight Adults.

BACKGROUND: The consumption of orange juice may lead to reduced oxidative stress and may enhance the antioxidant defense system. OBJECTIVE: The aim was to evaluate the effects of the intake of orange juice containing either normal (NPJ) or high (HPJ) concentrations of polyphenols (299 and 745 mg/d, respectively) on the antioxidant defense system, oxidative stress biomarkers, and clinical signs of metabolic syndrome in 100 nonsmoking subjects who were either overweight or obese. METHODS: A randomized, double-blind crossover study was conducted over two 12-wk periods with a 7-wk washout period. The effects on enzymatic and nonenzymatic blood antioxidant defense systems, urinary and plasma oxidative stress biomarkers, and clinical signs of metabolic syndrome were evaluated before and after an intervention with both of the orange juices. Paired t tests and linear mixed-effects models were used to evaluate the effects of juice, time, and interactions. RESULTS: The intake of either NPJ or HPJ led to a decrease in urinary 8-hydroxy-2'-deoxyguanosine (NPJ: 935 ± 134 to 298 ± 19 ng/mg creatinine; HPJ: 749 ± 84 to 285 ± 17 ng/mg creatinine), 8-iso-prostaglandin F2α (NPJ: 437 ± 68 to 156 ± 14 ng/mg creatinine; HPJ: 347 ± 43 to 154 ± 13 ng/mg creatinine), erythrocyte catalase, and glutathione reductase activities. A decrease was also observed in body mass index, waist circumference, and leptin (all P < 0.05). The NPJ intervention decreased systolic and diastolic blood pressures (systolic blood pressure: 128 ± 1 to 124 ± 2 mm Hg; diastolic blood pressure: 79 ± 1 to 76 ± 1 mm Hg), whereas the HPJ intervention increased erythrocyte superoxide dismutase (SOD) activity (17.7 ± 1.5 to 23.1 ± 1.7 U/mg hemoglobin). CONCLUSIONS: Our results show that the consumption of either NPJ or HPJ protected against DNA damage and lipid peroxidation, modified several antioxidant enzymes, and reduced body weight in overweight or obese nonsmoking adults. Only blood pressure and SOD activity were influenced differently by the different flavanone supplementations. This trial was registered at clinicaltrials.gov as NCT01290250.

Glycemic responses, appetite ratings and gastrointestinal hormone responses of most common breads consumed in Spain. A randomized control trial in healthy humans.

The present study was carried out to determine the glycemic index (GI), glycemic load (GL), insulinemic index (InI), appetite ratings and postprandial plasma concentrations of gastrointestinal hormones related to the control of food intake after the ingestion of the five most common breads consumed in Spain with different compositions and manufacturing processes. Twenty-two healthy adults participated in a randomized crossover study. The breads tested were Ordinary, Precooked-Frozen, Candeal-flour, Alfacar whites and Wholemeal. All breads portions were calculated to supply 50 g of available carbohydrates. In addition, 50 g of glucose was used as a reference. A linear mixed-effects model was used to compare data calculated for all breads with glucose load. The GI value varied from 61 for the Wholemeal, to Alfacar 68, Ordinary 76, and 78 and 86 for the Precooked-Frozen and Candeal-flour breads, respectively. Wholemeal and Alfacar had lower GI than glucose. All tested breads had a lower GL (ranged 9 to 18) compared with glucose. Wholemeal GL was similar to Alfacar, but lower than the other white breads. InI were significantly lower for all breads (ranged 68 to 73) compared with glucose, and similar among them. The intake of the Wholemeal bread led to a higher release of gastric inhibitory polypeptide compared with the Ordinary and Precooked breads and to a higher release of pancreatic polypeptide compared with the Precooked-Frozen bread. All breads affected appetite ratings similarly. In conclusion, based on GL, the Wholemeal bread would be expected to exert a favorable glycemic response.

An enriched, cereal-based bread affects appetite ratings and glycemic, insulinemic, and gastrointestinal hormone responses in healthy adults in a randomized, controlled trial.

BACKGROUND: Bread can contribute to the regulation of appetite. OBJECTIVE: The objective of this study was to investigate the appetite ratings and postprandial glucose, insulin, and gastrointestinal hormone responses related to hunger and satiety after the intake of a cereal-based bread. METHODS: A randomized, controlled crossover trial was conducted in 30 healthy adults (17 men and 13 women) aged 19-32 y with body mass index of 19.2-28.5. Each volunteer consumed the cereal-based bread and the control bread 2 times, with a 1-wk wash-out period, over a total of 4 sessions. The cereal-based bread contained a variety of cereal flours (wheat, oat, and spelt) and consisted of 22% dried fruits (figs, apricots, raisins, and prunes). It was also enriched with both fiber (7% from wheat cross-linked maltodextrins and pea) and protein (10-11% from wheat gluten and hydrolyzed wheat proteins). The control bread consisted of white bread with margarine and jam to control for energy density, fat, and sugar content. We measured appetite ratings using standardized visual analogue scales and glucose, insulin, and gastrointestinal hormone responses over a postprandial time of 4 h after the ingestion of each bread. Linear mixed-effects models were used to compare the areas under the curve (AUCs) for different variables. RESULTS: Consuming the cereal-based bread decreased prospective consumption more than consumption of the control bread (-5.3 ± 0.6 m · min and -4.4 ± 0.6 m · min, respectively; P = 0.02) and increased satiety more (6.2 ± 0.7 m · min and 5.2 ± 0.6 m · min, respectively; P = 0.04), although subsequent ad libitum energy intake 4 h later did not differ. Postprandial blood glucose, insulin, ghrelin, glucagon-like peptide 1 and gastric inhibitory polypeptide AUCs were lower after the ingestion of the cereal-based bread, whereas the pancreatic polypeptide AUC was higher than with the control bread (P < 0.05). CONCLUSIONS: Consumption of the cereal-based bread contributed to appetite control by reducing hunger and enhancing satiety. In addition, consumption of this bread improved glycemic, insulinemic, and gastrointestinal hormone responses in healthy adults. This trial was registered at clinicaltrials.gov as NCT02090049.